Nygren, Jonas

Abstract Background This is the fourth updated Enhanced Recovery After Surgery (ERAS ® ) Society guideline presenting a consensus for optimal perioperative care in colorectal surgery and providing graded recommendations for each ERAS item within the ERAS ® protocol. Methods A wide database search on English literature publications was performed. Studies on each item within the protocol were selected with particular attention paid to meta‐analyses, randomised controlled trials and large prospective cohorts and examined, reviewed and graded according to Grading of Recommendations, Assessment, Development and Evaluation (GRADE) system. Results All recommendations on ERAS ® protocol items are based on best available evidence; good‐quality trials; meta‐analyses of good‐quality trials; or large cohort studies. The level of evidence for the use of each item is presented accordingly. Conclusions The evidence base and recommendation for items within the multimodal perioperative care pathway are presented by the ERAS ® Society in this comprehensive consensus review.

Triiodothyronine (T3) increases O2 and nutrient flux through mitochondria (Mito) of many tissues, but it is unclear whether ATP synthesis is increased, particularly in different types of skeletal muscle, because variable changes in uncoupling proteins (UCP) and enzymes have been reported. Thus Mito ATP production was measured in oxidative and glycolytic muscles, as well as in liver and heart, in rats administered T3 for 14 days. Relative to saline-treated controls, T3 rats had 80, 168, and 62% higher ATP production in soleus muscle, liver, and heart, respectively, as well as higher activities of citrate synthase (CS; 63, 90, 25%) and cytochrome c oxidase (COX; 119, 225, 52%) in the same tissues (all P < 0.01). In plantaris muscle of T3 rats, CS was only slightly higher (17%, P < 0.05) than in controls, and ATP production and COX were unaffected. mRNA levels of COX I and III were 33 and 47% higher in soleus of T3 rats ( P < 0.01), but there were no differences in plantaris. In contrast, UCP2 and -3 mRNAs were 2.5- to 14-fold higher, and protein levels were 3- to 10-fold higher in both plantaris and soleus of the T3 group. We conclude that T3 increases oxidative enzymes and Mito ATP production and Mito-encoded transcripts in oxidative but not glycolytic rodent tissues. Despite large increases in UCP expression, ATP production was enhanced in oxidative tissues and maintained in glycolytic muscle of hyperthyroid rats.

Elective surgery was performed after overnight fasting, a routine that may affect the metabolic response to surgery. We investigated the effects of insulin and glucose infusions before and during surgery on postoperative substrate utilization and insulin sensitivity. Seven patients were given insulin and glucose infusions 3 h before and during surgery (insulin group), and a control group of six patients underwent surgery after fasting overnight. Insulin sensitivity and glucose kinetics (d-[6,6-2H2]glucose) were measured before and immediately after surgery using a hyperinsulinemic, normoglycemic clamp. Glucose infusion rates and whole body glucose disposal decreased after surgery in the control group (−40 and −29%, respectively), whereas no significant change was found in the insulin group (+16 and +25%). Endogenous glucose production remained unchanged in both groups. Postoperative changes in cortisol, glucagon, fat oxidation, and free fatty acids were attenuated in the insulin group (vs. control). We conclude that perioperative insulin and glucose infusions minimize the endocrine stress response and normalize postoperative insulin sensitivity and substrate utilization.

To investigate the underlying molecular mechanisms for surgery-induced insulin resistance in skeletal muscle, six otherwise healthy patients undergoing total hip replacement were studied before, during, and after surgery. Patients were studied under basal conditions and during physiological hyperinsulinemia (60 μU/ml). Biopsies of vastus lateralis muscle were used to measure GLUT-4 translocation, glucose transport, and glycogen synthase activities. Surgery reduced insulin-stimulated glucose disposal ( P < 0.05) without altering the insulin-stimulated increase in glucose oxidation or suppression of endogenous glucose production. Preoperatively, insulin infusion increased plasma membrane GLUT-4 in all six subjects ( P < 0.05), whereas insulin-stimulated GLUT-4 translocation only occurred in three patients postoperatively (not significant). Moreover, nonoxidative glucose disposal rates and basal levels of glycogen synthase activities in muscle were reduced postoperatively ( P< 0.05). These findings demonstrate that peripheral insulin resistance develops immediately postoperatively and that this condition might be associated with perturbations in insulin-stimulated GLUT-4 translocation as well as nonoxidative glucose disposal, presumably at the level of glycogen synthesis.

1. Insulin resistance after surgery has been shown to be related to several important derangements in protein and fat metabolism. However, mechanisms of impaired glucose tolerance after surgery remain ill-defined. 2. Insulin sensitivity and glucose kinetics (6,62H2-glucose) were studied in seven patients before and after elective surgery (surgery group), by two step-hyperinsulinaemic (0.3 and 0.8 munits kg−1 min−1), normoglycaemic (4.5 mmol/l) clamps. Six healthy subjects were studied, using the same protocol, before and after a similar period of bed rest and hypocaloric nutrition (fast/bed rest group) to delineate the effects of surgery per se. 3. Basal endogenous glucose production and whole-body glucose disposal was higher after surgery (P &lt; 0.001), whereas no change was found after fast/bed rest. During glucose clamps, the glucose infusion rates required to maintain normoglycaemia and whole-body glucose disposal decreased (P &lt; 0.001) after surgery, while endogenous glucose production increased (P &lt; 0.001). In the control subjects, levels of endogenous glucose production remained unchanged after fast/bed rest. In contrast, glucose infusion rates and whole-body glucose disposal during glucose clamps also decreased after fast/bed rest (P &lt; 0.01). However, the relative decrease in both these parameters was greater after surgery compared with after fast/bed rest (P &lt; 0.01). 4. After surgery, energy expenditure and fat oxidation increased (P &lt; 0.001), whereas glucose oxidation decreased (P &lt; 0.05). No significant change was found in glucose utilization postoperatively. After fast/bed rest, no change was found in energy expenditure. However, fat oxidation increased (P &lt; 0.01), whereas glucose oxidation and glucose utilization decreased (P &lt; 0.05). 5. In conclusion, impaired glucose tolerance develops after surgery as a result of decreased insulin-stimulated whole-body glucose disposal as well as increased endogenous glucose release. Despite the increase in endogenous glucose production, the reduction in endogenous glucose production with each elevation of insulin was unaffected by surgery. Perioperative bed rest and/or hypocaloric nutrition contribute to the decrease in insulin-stimulated whole-body glucose disposal in the postoperative state, whereas these factors have no effects on endogenous glucose production.

Thyroid hormone excess is associated with increased energy expenditure. The contributions of increases in spontaneous physical activity and nonexercise activity thermogenesis (NEAT) to this effect have not been defined. To address the hypothesis that hyperthyroidism is associated with increased spontaneous physical activity and NEAT, we rendered rats hyperthyroid by using continuous infusion of high-dose triiodothyronine for 14 days and measured the effects on physical activity and NEAT. On day 14, in the hyperthyroid group the mean ± SD triiodothyronine concentration was 755 ± 137 (range 574–919) ng/dl and in the control group 59 ± 0.5 (58–59) ng/dl. Over the 14-day treatment period, mean spontaneous physical activity increased in the hyperthyroid rats from 24 ± 7 to 36 ± 6 activity units (AU)/min; P < 0.001 but did not increase in the controls (23 ± 7 vs. 22 ± 4 AU/min). Also, over the 14-day period, daily NEAT increased in the hyperthyroid rats from 8.1 ± 2.8 to 19.7 ± 5.0 kcal/day ( P < 0.001) but did not increase in the controls (8.7 ± 3.5 cf 9.4 ± 1.7 kcal/day; not significant). In conclusion, hyperthyroidism is associated with increased spontaneous physical activity and NEAT.

Rodent skeletal muscle mitochondrial DNA has been shown to be a potential site of oxidative damage during aging. Caloric restriction (CR) is reported to reduce oxidative stress and prolong life expectancy in rodents. Gene expression profiling and measurement of mitochondrial ATP production capacity were performed in skeletal muscle of male rats after feeding them either a control diet or calorie-restricted diet (60% of control diet) for 36 wk to determine the potential mechanism of the beneficial effects of CR. CR enhanced the transcripts of genes involved in reactive oxygen free radical scavenging function, tissue development, and energy metabolism while decreasing expression of those genes involved in signal transduction, stress response, and structural and contractile proteins. Real-time PCR measurments confirmed the changes in transcript levels of cytochrome- c oxidase III, superoxide dismutase (SOD)1, and SOD2 that were noted by the microarray approach. Mitochondrial ATP production and citrate synthase were unaltered by the dietary changes. We conclude that CR alters transcript levels of several genes in skeletal muscle and that mitochondrial function in skeletal muscle remains unaltered by the dietary intervention. Alterations in transcripts of many genes involved in reactive oxygen scavenging function may contribute to the increase in longevity reported with CR.

High-fat diets are reported to increase oxidative stress in a variety of tissues, whereas antioxidant supplementation prevents many diseases attributed to high-fat diet. Rodent skeletal muscle mitochondrial DNA has been shown to be a potential site of oxidative damage. We hypothesized that the effects of a high-fat diet on skeletal muscle DNA functions would be attenuated or partially reversed by antioxidant supplementation. Gene expression profiling and measurement of mitochondrial ATP production capacity were performed in skeletal muscle from male rats after feeding one of three diets (control, high-fat diet with or without antioxidants) for 36 wk. The high-fat diet altered transcript levels of 18 genes of 800 surveyed compared with the control-fed rats. Alterations included reduced expression of genes involved in free-radical scavenging and tissue development and increased expression of stress response and signal transduction genes. The magnitude of these alterations due to high-fat diet was reduced by antioxidant supplementation. Real-time PCR measurements confirmed the changes in transcript levels of cytochrome c oxidase subunit III and superoxide dismutase-1 and -2 noted by microarray approach. Mitochondrial ATP production was unaltered by dietary changes or antioxidant supplemention. It is concluded that the high-fat diet increases the transcription of genes involved in stress response but reduces those of free-radical scavenger enzymes, resulting in reduced DNA repair/metabolism (increased DNA damage). Antioxidants partially prevent these changes. Mitochondrial functions in skeletal muscle remain unaltered by the dietary intervention due to many adaptive changes in gene transcription.

OBJECTIVE Because direct adipose tissue free fatty acid (FFA) storage may contribute to body fat distribution, we measured FFA (palmitate) storage rates and fatty acid (FA) storage enzymes/proteins in omental and abdominal subcutaneous fat. RESEARCH DESIGN AND METHODS Elective surgery patients received a bolus of [1-14C]palmitate followed by omental and abdominal subcutaneous fat biopsies to measure direct FFA storage. Long chain acyl-CoA synthetase (ACS) and diacylglycerol acyltransferase activities, CD36, fatty acid-binding protein, and fatty acid transport protein 1 were measured. RESULTS Palmitate tracer storage (dpm/g adipose lipid) and calculated palmitate storage rates were greater in omental than abdominal subcutaneous fat in women (1.2 ± 0.8 vs. 0.7 ± 0.4 μmol ⋅ kg adipose lipid−1 ⋅ min−1, P = 0.005) and men (0.7 ± 0.2 vs. 0.2 ± 0.1, P &lt; 0.001), and both were greater in women than men (P &lt; 0.0001). Abdominal subcutaneous adipose tissue palmitate storage rates correlated with ACS activity (women: r = 0.66, P = 0.001; men: r = 0.70, P = 0.007); in men, CD36 was also independently related to palmitate storage rates. The content/activity of FA storage enzymes/proteins in omental fat was dramatically lower in those with more visceral fat. In women, only omental palmitate storage rates were correlated (r = 0.54, P = 0.03) with ACS activity. CONCLUSIONS Some adipocyte FA storage factors correlate with direct FFA storage, but sex differences in this process in visceral fat do not account for sex differences in visceral fatness. The reduced storage proteins in those with greater visceral fat suggest that the storage factors we measured are not a predominant cause of visceral adipose tissue accumulation.

To determine the in vivo effect of amino acids (AAs) alone or in combination with insulin on splanchnic and muscle protein dynamics, we infused stable isotope tracers of AAs in 36 healthy subjects and sampled from femoral artery and vein and hepatic vein. The subjects were randomized into six groups and were studied at baseline and during infusions of saline (group 1), insulin (0.5 mU · kg−1 · min−1) (group 2), insulin plus replacement of AAs (group 3) insulin plus high-dose AAs (group 4), or somatostatin and baseline replacement doses of insulin, glucagon and GH plus high dose of AAs (group 5) or saline (group 6). Insulin reduced muscle release of AAs mainly by inhibition of protein breakdown. Insulin also enhanced AA-induced muscle protein synthesis (PS) and reduced leucine transamination. The main effect of AAs on muscle was the enhancement of PS. Insulin had no effect on protein dynamics or leucine transamination in splanchnic bed. However, AAs reduced protein breakdown and increased synthesis in splanchnic bed in a dose-dependent manner. AAs also enhanced leucine transamination in both splanchnic and muscle beds. Thus insulin’s anabolic effect was mostly on muscle, whereas AAs acted on muscle as well as on splanchnic bed. Insulin achieved anabolic effect in muscle by inhibition of protein breakdown, enhancing AA-induced PS, and reducing leucine transamination. AAs largely determined protein anabolism in splanchnic bed by stimulating PS and decreasing protein breakdown.